Quinoline Inhibitor of the Macrophage Stimulating 1 Receptor MSTR1

ABSTRACT

The compound N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide 
     
       
         
         
             
             
         
       
     
     and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,
 
is an inhibitor of RON and can be employed, for the treatment of cancer.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to the compoundN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidethat is capable of inhibiting one or more kinases. The compound findapplications in the treatment of a variety of disorders, includingcancer, septic shock, Primary open Angle Glaucoma (POAG), hyperplasia,rheumatoid arthritis, psoriasis, artherosclerosis, retinopathy,osteoarthritis, endometriosis, chronic inflammation, and/orneurodegenerative diseases such as Alzheimers disease.

The present invention relates toN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand to the use ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidein which the inhibition, regulation and/or modulation of signaltransduction by kinases, in particular receptor tyrosine kinases, playsa role, furthermore to pharmaceutical compositions which comprise thecompound, and to the use of the compound for the treatment ofkinase-induced diseases.

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as but notlimited to cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

In particular, the present invention relates toN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand to the use ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidein which the inhibition, regulation and/or modulation of signaltransduction by RON (récepteur d'origine nantais) plays a role.

One of the principal mechanisms by which cellular regulation is effectedis through the transduction of extracellular signals across themembrane, that in turn modulate biochemical pathways within the cell.Protein phosphorylation represents one course by which intracellularsignals are propagated from molecule to molecule resulting finally in acellular response. These signal transduction cascades are highlyregulated and often overlap, as is evident from the existence of manyprotein kinases as well as phosphatases. Phosphorylation of proteinsoccurs predominantly at serine, threonine or tyrosine residues, andprotein kinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

Diseases caused by protein kinases are characterised by anomalousactivity or hyperactivity of such protein kinases. Anomalous activityrelates to either: (1) expression in cells which do not usually expressthese protein kinases; (2) increased kinase expression, which results inundesired cell proliferation, such as cancer; (3) increased kinaseactivity, which results in undesired cell proliferation, such as cancer,and/or in hyperactivity of the corresponding protein kinases.Hyperactivity relates either to amplification of the gene which encodesfor a certain protein kinase, or the generation of an activity levelwhich can be correlated with a cell proliferation disease (i.e. theseverity of one or more symptoms of the cell proliferation diseaseincreases with increasing kinase level). The bioavailability of aprotein kinase may also be influenced by the presence or absence of aset of binding proteins of this kinase.

S. Raeppel et al. describe potent RON receptor tyrosine kinaseinhibitors with residual activity against the closely related c-Met orpotent dual inhibitory activity against RON and c-Met, such asN-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridine-7-oxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides,in Bioorganic & Medicinal Chemistry Letters 20 (2010) 2745-2749 aspotential anti-cancer therapeutics.

ImClone Systems (now a division of Eli Lilly & Co.) developed IMC-41A10,a human IgG1 monoclonal antibody that binds with high affinity to humanRON RTK (receptor tyrosine kinase) and blocks MSP (macrophagestimulating protein) ligand binding (J. M. O'Toole et al., Cancer Res.2006, 66, 9162). IMC-41A10 inhibited tumor growth by 50-60% in severalhuman xenograft tumor models including colon, lung and pancreaticcarcinoma models.

Small molecule inhibitors of RON have been described as well. Thesechemical entities inhibit both RON and the closely related c-Met kinase.c-Met is found to be activated in a large number of different cancersand small molecule inhibitors targeting Met/RON are presently underclinical evaluation in patients with solid tumors:

-   (a) For recent reviews see: P. C. Ma, G. Maulik, J. Christensen    and R. Salgia, Cancer Metastasis Rev. 22 (2003), p. 309.-   (b) C. W. Birchmeier, W. Birchmeier, E. Gherardi and G. F. Vande    Woude, Nat. Rev. Mol. Cell Biol. 4 (2003), p. 915.-   (c) J. G. Christensen, J. Burrows and R. Salgia, Cancer Lett. 225    (2005), p. 1.-   (d) S. Corso, P. M. Comoglio and S. Giordano, Trends Mol. Med. 11    (2005), p. 284.-   (e) C. Boccaccio and P. M. Comoglio, Nat. Rev. Cancer 6 (2006), p.    637.-   (f) B. Peruzzi and D. P. Bottaro, Clin. Cancer Res. 12 (2006), p.    3657.-   (g) B. S. Knudsen and G. Vande Woude, Cur. Opin. Gen. Dev. 18    (2008), p. 87.-   (h) L. Toschi and P. A. Jänne, Clin. Cancer Res. 14 (2008), p. 5941.-   (i) I. Dussault and S. F. Belton, Anti-Cancer Agents Med. Chem. 9    (2009), p. 221.-   (j) N. A. Cipriani, O. O. Abidoye, E. Vokes and R. Salgia, Lung    Cancer 63 (2009), p. 169.-   (k) J. Porter, Expert Opin. Ther. Patents 20 (2010), p. 159.-   (l) T. L. Underiner, T. Herbertz and S. J. Miknyoczki, Anti-Cancer    Agents Med. Chem. 10 (2010), p. 7.

For example, a potent small-molecule dual inhibitor of c-Met/RON wasdisclosed by Amgen:

-   J. Zhang et al., Cancer Res. 2008, 68, 6680;-   L. Liu et al., J. Med. Chem. 2008, 51, 3688.

This quinoline based compound having the1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamidehead group

inhibits both Met and RON enzymes and demonstrates anti-tumor activityin a colorectal xenograft model in mice.

Bristol-Myers Squib describes BMS-777607

as a new pyridine based selective and orally efficacious inhibitor ofthe Met/RON kinase superfamily that has advanced into phase I clinicaltrials (G. M. Schroeder et al., J. Med. Chem. 2009, 52, 1251).

Accordingly, the compound according to the invention or apharmaceutically acceptable salt thereof are administered for thetreatment of cancer, including solid carcinomas, such as, for example,carcinomas (for example of the lungs, pancreas, thyroid, bladder orcolon), myeloid diseases (for example myeloid leukaemia) or adenomas(for example villous colon adenoma).

The tumours furthermore include monocytic leukaemia, brain, urogenital,lymphatic system, stomach, laryngeal and lung carcinoma, including lungadenocarcinoma and small-cell lung carcinoma, pancreatic and/or breastcarcinoma.

The compound according to the invention is furthermore suitable for thetreatment of immune deficiency induced by HIV-1 (Human ImmunodeficiencyVirus Type 1).

Cancer-like hyperproliferative diseases are to be regarded as braincancer, lung cancer, squamous epithelial cancer, bladder cancer, stomachcancer, pancreatic cancer, liver cancer, renal cancer, colorectalcancer, breast cancer, head cancer, neck cancer, oesophageal cancer,gynaecological cancer, thyroid cancer, lymphomas, chronic leukaemia andacute leukaemia. In particular, cancer-like cell growth is a diseasewhich represents a target of the present invention. The presentinvention therefore relates to the compound according to the inventionas medicament and/or medicament active ingredient in the treatmentand/or prophylaxis of the said diseases and to the use of the compoundaccording to the invention for the preparation of a pharmaceutical forthe treatment and/or prophylaxis of the said diseases and to a processfor the treatment of the said diseases comprising the administration ofthe compound according to the invention to a patient in need of such anadministration.

It can be shown that the compound according to the invention has anantiproliferative action. The compound according to the invention isadministered to a patient having a hyperproliferative disease, forexample to inhibit tumour growth, to reduce inflammation associated witha lymphoproliferative disease, to inhibit transplant rejection orneurological damage due to tissue repair, etc. The present compound issuitable for prophylactic or therapeutic purposes. As used herein, theterm “treatment” is used to refer to both the prevention of diseases andthe treatment of pre-existing conditions. The prevention ofproliferation/vitality is achieved by administration of the compoundaccording to the invention prior to the development of overt disease,for example for preventing tumour growth. Alternatively, the compound isused for the treatment of ongoing diseases by stabilising or improvingthe clinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of a human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro testing.Typically, a culture of the cell is incubated with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitcell proliferation, cell vitality or migration, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from a biopsy sample. The amount of cells remainingafter the treatment are then determined. The dose varies depending onthe specific compound used, the specific disease, the patient status,etc. A therapeutic dose is typically sufficient considerably to reducethe undesired cell population in the target tissue, while the viabilityof the patient is maintained. The treatment is generally continued untila considerable reduction has occurred, for example an at least about 50%reduction in the cell burden, and may be continued until essentially nomore undesired cells are detected in the body.

There are many diseases associated with deregulation of cellproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compound accordingto the invention is suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions.

Occlusive graft vascular diseases of interest include atherosclerosis,coronary vascular disease after grafting, vein graft stenosis,perianastomatic prosthetic restenosis, restenosis after angioplasty orstent placement, and the like.

In addition, the compound according to the invention can be used toachieve additive or synergistic effects in certain existing cancerchemotherapies and radiotherapies and/or to restore the efficacy ofcertain existing cancer chemotherapies and radiotherapies.

The term “method” refers to manners, means, techniques and proceduresfor accomplishing a given task including, but not limited to, thosemanners, means, techniques and procedures either known to, or readilydeveloped from known manners, means, techniques and procedures bypractitioners of the chemical, pharmacological, biological, biochemicaland medical arts.

The term “administering” as used herein refers to a method for bringingthe compound of the present invention and a target kinase together insuch a manner that the compound can affect the enzyme activity of thekinase either directly; i.e., by interacting with the kinase itself orindirectly; i.e., by interacting with another molecule on which thecatalytic activity of the kinase is dependent. As used herein,administration can be accomplished either in vitro, i.e. in a test tube,or in vivo, i.e., in cells or tissues of a living organism.

Herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a disease ordisorder, substantially ameliorating clinical symptoms of a disease ordisorder or substantially preventing the appearance of clinical symptomsof a disease or disorder.

Herein, the term “preventing” refers to a method for barring an organismfrom acquiring a disorder or disease in the first place.

For the compound used in this invention, a therapeutically effectiveamount, also referred to herein as a therapeutically effective dose, canbe estimated initially from cell culture assays. For example, a dose canbe formulated in animal models to achieve a circulating concentrationrange that includes the IC50 or the IC100 as determined in cell culture.Such information can be used to more accurately determine useful dosesin humans. Initial dosages can also be estimated from in vivo data.Using these initial guidelines one of ordinary skill in the art coulddetermine an effective dosage in humans.

Moreover, toxicity and therapeutic efficacy of the compounds describedherein can be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., by determining the LD50 and theED50. The dose ratio between toxic and therapeutic effect is thetherapeutic index and can be expressed as the ratio between LD50 andED50. The data obtained from these cell cultures assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in human. The dosage lies preferably within a range of circulatingconcentrations that include the ED50 with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition, (see, e.g.,Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics,chapter 1, page 1).

Dosage amount and interval may be adjusted individually to provideplasma levels of the active compound which are sufficient to maintaintherapeutic effect. Usual patient dosages for oral administration rangefrom about 50-2000 mg/kg/day, commonly from about 100-1000 mg/kg/day,preferably from about 150-700 mg/kg/day and most preferably from about250-500 mg/kg/day.

Preferably, therapeutically effective serum levels will be achieved byadministering multiple doses each day. In cases of local administrationor selective uptake, the effective local concentration of the drug maynot be related to plasma concentration. One skilled in the art will beable to optimize therapeutically effective local dosages without undueexperimentation.

Preferred diseases or disorders that the compound described herein maybe useful in preventing, treating and/or studying are cell proliferativedisorders, especially cancer such as, but not limited to, papilloma,blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer,prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neckcancer, skin cancer, liver cancer, bladder cancer, breast cancer, lungcancer, uterus cancer, prostate cancer, testis carcinoma, colorectalcancer, thyroid cancer, pancreatic cancer, gastric cancer,hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease andBurkitt's disease.

PRIOR ART

Other heterocyclic derivatives and their use as anti-tumour agents havebeen described in WO 2006/116713 A1.

S. Raeppel et al. describe potent RON receptor tyrosine kinaseinhibitors in Bioorganic & Medicinal Chemistry Letters 20 (2010)2745-2749 as potential anti-cancer therapeutics.

SUMMARY OF THE INVENTION

The invention relates to the compoundN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide

and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), salts, the enantiomers, the racemates, thediastereomers and the hydrates and solvates of the compound. The termsolvates of the compound is taken to mean adductions of inert solventmolecules onto the compounds which form owing to their mutual attractiveforce. Solvates are, for example, mono- or dihydrates or alkoxides.

Of course, the invention also relates to the solvates of the salts.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compound according to the invention and alsoso-called prodrug compounds. The term prodrug derivatives is taken tomean the compound according to the invention which has been modified bymeans of, for example, alkyl or acyl groups, sugars or oligopeptides andwhich is rapidly cleaved in the organism to form the effective compoundaccording to the invention.

These also include biodegradable polymer derivatives of the compoundaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the advance of a disease, condition or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention relates toN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand salts thereof and to a process for the preparation ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand pharmaceutically usable salts, tautomers and stereoisomers thereof,characterised in that

is reacted with

and/orN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideis converted into one of its salts.

N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand also the starting materials for their preparation are, in addition,prepared by methods known per se, as described in the literature (forexample in the standard works, such as Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag,Stuttgart), to be precise under reaction conditions which are known andsuitable for the said reactions. Use can also be made here of variantsknown per se which are not mentioned here in greater detail.

N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidecan preferably be obtained by reacting5-ethyl-1-pyrimidin-5-yl-pyrazole-4-carbonyl chloride with4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluoro-aniline.

In 5-ethyl-1-pyrimidin-5-yl-pyrazole-4-carbonyl chloride the Cl may bereplaced by Br, I or a free or reactively modified OH group, such as,for example, an activated ester, an imidazolide or alkylsulfonyloxyhaving 1-6 C atoms (preferably methyl-sulfonyloxy ortrifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms(preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°. Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbontetrachloride, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, suchas acetone or butanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to pyridine, acetonitrile,dichloromethane and/or DMF.

Pharmaceutical Salts and Other Forms

The said compound according to the invention can be used in its finalnon-salt form. On the other hand, the present invention also encompassesthe use of the compound in the form of its pharmaceutically acceptablesalts, which can be derived from various organic and inorganic acids andbases by procedures known in the art.

Pharmaceutically acceptable salt forms of the compound according to theinvention are for the most part prepared by conventional methods. In thecase ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide,acid-addition salts can be formed by treating the compound withpharmaceutically acceptable organic and inorganic acids, for examplehydrogen halides, such as hydrogen chloride, hydrogen bromide orhydrogen iodide, other mineral acids and corresponding salts thereof,such as sulfate, nitrate or phosphate and the like, and alkyl- andmonoarylsulfonates, such as ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like.Accordingly, pharmaceutically acceptable acid-addition salts of thecompound include the following: acetate, adipate, alginate, arginate,aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite,bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride,chlorobenzoate, citrate, cyclopentane-propionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,fumarate, galacterate (from mucic acid), galacturonate,gluco-heptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide,isethionate, isobutyrate, lactate, lactobionate, malate, maleate,malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate,monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,3-phenylpropionate, phosphate, phosphonate, phthalate, but this does notrepresent a restriction.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideare prepared by bringing the free base form into contact with asufficient amount of the desired acid, causing the formation of the saltin a conventional manner. The free base can be regenerated by bringingthe salt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts other-wise correspond tothe respective free base forms thereof.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprisesN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidein the form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at leastN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand/or pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, and optionallyexcipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, can likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand the pharmaceutically usable salts, tautomers and stereoisomersthereof can also be administered in the form of liposome deliverysystems, such as, for example, small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom various phospholipids, such as, for example, cholesterol,stearylamine or phosphatidylcholines.

N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand the pharmaceutically usable salts, tautomers and stereoisomersthereof can also be delivered using monoclonal antibodies as individualcarriers to which the compound molecules are coupled. The compounds canalso be coupled to soluble polymers as targeted medicament carriers.Such polymers may encompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompound may furthermore be coupled to a class of biodegradable polymerswhich are suitable for achieving controlled release of a medicament, forexample polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyricacid, polyorthoesters, polyacetals, polydihydroxypyrans,polycyanoacrylates and crosslinked or amphipathic block copolymers ofhydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidedepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at leastN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand/or the pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, and at least onefurther medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

(a) an effective amount ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand/or the pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios,and(b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amountN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand/or the pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, and an effectiveamount of a further medicament active ingredient in dissolved orlyophilised form.

Use

The invention relates toN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidefor the use for the treatment of cancer, septic shock, Primary openAngle Glaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis,artherosclerosis, retinopathy, osteoarthritis, endometriosis, chronicinflammation, and/or neurodegenerative diseases such as Alzheimersdisease.

The invention relates to the use ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidefor the preparation of a medicament for the treatment of cancer, septicshock, Primary open Angle Glaucoma (POAG), hyperplasia, rheumatoidarthritis, psoriasis, artherosclerosis, retinopathy, osteoarthritis,endometriosis, chronic inflammation, and/or neurodegenerative diseasessuch as Alzheimers disease.

The invention relates to a method of treating a mammal having a diseaseselected from cancer, septic shock, Primary open Angle Glaucoma (POAG),hyperplasia, rheumatoid arthritis, psoriasis, artherosclerosis,retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/orneurodegenerative diseases such as Alzheimers disease, wherein themethod comprises administering to a mammal a therapeutically effectiveamount ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide.

N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideis suitable as pharmaceutical active ingredients for mammals, especiallyfor humans, in the treatment and control of cancer diseases andinflammatory diseases.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow active agents such as anti IgM to induce a cellularresponse such as expression of a surface marker, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from blood or from a biopsy sample. The amount ofsurface marker expressed are assessed by flow cytometry using specificantibodies recognising the marker.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compound according to the invention can alsobe used as reagents for testing kinase-dependent signal transductionpathways in animals and/or cell culture models or in the clinicaldiseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

The present invention encompasses the use ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand/or physiologically acceptable salts, tautomers and solvates thereoffor the preparation of a medicament for the treatment or prevention ofcancer. Preferred carcinomas for the treatment originate from the groupcerebral carcinoma, urogenital tract carcinoma, carcinoma of thelymphatic system, stomach carcinoma, laryngeal carcinoma and lungcarcinoma bowel cancer. A further group of preferred forms of cancer aremonocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas,pancreatic cancer, glioblastomas and breast carcinoma.

Also encompassed is the use ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand/or physiologically acceptable salts, tautomers and solvates thereoffor the preparation of a medicament for the treatment and/or control ofa tumour-induced disease in a mammal, in which to this method atherapeutically effective amount of a compound according to theinvention is administered to a sick mammal in need of such treatment.The therapeutic amount varies according to the particular disease andcan be determined by the person skilled in the art without undue effort.

Particular preference is given to the use for the treatment of adisease, where the cancer disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thesquamous epithelium, the bladder, the stomach, the kidneys, of head andneck, the oesophagus, the cervix, the thyroid, the intestine, the liver,the brain, the prostate, the urogenital tract, the lymphatic system, thestomach, the larynx and/or the lung.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The invention furthermore relates to the use of the compounds accordingto the invention for the treatment of bone pathologies, where the bonepathology originates from the group osteosarcoma, osteoarthritis andrickets.

N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidemay also be administered at the same time as other well-knowntherapeutic agents that are selected for their particular usefulnessagainst the condition that is being treated.

The present compound is also suitable for combination with knownanti-cancer agents. These known anti-cancer agents include thefollowing: oestrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors, HIV protease inhibitors, reverse transcriptase inhibitorsand further angiogenesis inhibitors. The present compounds areparticularly suitable for administration at the same time asradiotherapy.

“Oestrogen receptor modulators” refers to compounds which interfere withor inhibit the binding of oestrogen to the receptor, regardless ofmechanism. Examples of oestrogen receptor modulators include, but arenot limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone and SH646.

“Androgen receptor modulators” refers to compounds which interfere withor inhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere withor inhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenylretinamide.

“Cytotoxic agents” refers to compounds which result in cell deathprimarily through direct action on the cellular function or inhibit orinterfere with cell myosis, including alkylating agents, tumour necrosisfactors, intercalators, microtubulin inhibitors and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosylate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methylpyridine)platinum, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride,diarisidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exobenzylidenechartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)-dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxyetoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(di-methylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylene-dioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-amino-ethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

“Antiproliferative agents” include antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 andantimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-mannohepto-pyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also include monoclonal antibodies to growth factors other thanthose listed under “angiogenesis inhibitors”, such as trastuzumab, andtumour suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

Test for the Inhibition of RON

Inhibition of MSP (Macrophage Stimulating Protein) Induced pRON inCellular Assays

To determine potency and efficacy of RON kinase inhibitors in inhibitingligand induced RON phosphorylation,N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamidewas tested in cell based assays as described below. Inhibition of ligandinduced pRON (phosphoRON) in MDA-MB453 cells (cell basedelectrochemiluminescence assay (ECLA)): MDA-MB453 cells (DSMZ ACC65)were serum starved, pretreated with 1001IM Sodium Orthovanadate (1 h,37° C., 5% CO₂) and pre-incubated with compounds (serial dilutions,starting concentration 30 μM) in serum-free media for 45 min at 37° C.,5% CO₂. Cells were stimulated with 250 ng/ml MSP (R&D Systems, #4306-MS)for 20 min, supernatants discarded and cells lysed in cold NP-40 lysisbuffer (1% NP-40, 20 mM Tris, pH8.0, 137 mM NaCl, 10% glycerole, 2 mMEDTA, protease inhibitor cocktail set III (Calbiochem), phosphataseinhibitor cocktail set II (Calbiochem)). MA6000 96 well plates (MSD, #L15XB) were blocked with 3% block A (MSD) in PBS, pH7.4, 0.05% Tween20and coated with RON specific capture antibody (R&D Systems, # MAB691).Cell lysates were added and incubated for 2 h at room temperature (RT).Biotinylated anti-phospho Tyrosine antibody (R&D Systems, # BAM1676) andsulfo tag streptavidin reagent (MSD, #R32AD) were used for detection.

In-Vitro (Enzyme) Assay for Determination of the Efficacy of Inhibitorsof RON Kinase-Mediated Effects

The kinase assay was carried out as 384-well FlashPlate assay. As testplates 384-well streptavidine coated FlashPlate microtitre plates fromPerkin Elmer (USA) were used. The components of the kinase reaction werepipetted into the assay plate. 4.5 nM of GST tagged human recombinantRON kinase (Life technologies), 500 nM of biotinylated peptide substrateRDILDREYYSVQQHRH-amide (autophosphorylation site derived peptidesubstrate, custom-made) and 2 μM of ATP (with 0.5 μCi of <33>P-ATP/well)were incubated in a total volume of 50 μl (50 mM of HEPES, 5 mM ofMgCl2, 2 mM of DTT, 0.1% of BSA, 0.01% Igepal®CA630, 1% DMSO, pH 7.5) inthe presence or absence of test substance (10 concentrations) at 22[deg.] C for 30 min. The reaction was stopped using 50 μl of 200 mM EDTAsolution. After incubation for a further 80 min at room temperature, thesupernatants were removed by suction, and the wells were washed threetimes with 100 μl of 0.9% NaCl solution each time. The radioactivity wasmeasured using a Topcount scintillation counter (PerkinElmer, USA). TheIC50 values were calculated using Assay explorer (Table X).

The preparation ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideis carried out analogously to the following Scheme 1.

5-Hydrazinylpyrimidine A2 is obtained by copper-catalyzed reaction ofpyrimidine-5-boronic acid with di-tert-butyl-azodicarboxylate.Subsequent reaction of A2 with A1 yields the pyrazole A3. Finally,hydrolysis of A3 and subsequent acid chloride formation yields A5. Thereaction of aniline 1 and acid chloride A5 is carried out in thepresence of a base like pyridine and optionally in an inert solvent likeDCM. The acid chloride A5 can be prepared from the carboxylic acid viastandard procedures, using thionyl chloride or oxalyl chloride asreagents. Alternatively, carboxylic acid A4 can be directly coupled withaniline 1 under standard procedures, such as using HBTU or HATU to giveA6.

Preparation ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide

Abbreviations used in the description of the chemistry and in theExample that follow are:

ACN (acetonitrile); br (broad); CDCl₃ (deuterated chloroform); DCM(dichloromethane); DMF (dimethylformamide); DMSO (dimethyl sulfoxide);eq. (equivalent); ES (electrospray); EtOAc (ethyl acetate); EtOH(ethanol); HCl (hydrochloric acid); HOAc (acetic acid); KOH (potassiumhydroxide); MeOH (methanol); MS (mass spectrometry); NaHCO₃ (sodiumhydrogencarbonate); NMR (nuclear magnetic resonance; PE (petroleumether); RT (room temperature); sat. aq. (saturated aqueous); SiO₂(silica gel); THF (tetrahydrofuran).

Step 1: Ethyl 2-((dimethylamino)methylene)-3-oxopentanoate (A1)

N,N-Dimethylformamide dimethyl acetal (19.9 g, 166.5 mmol, 1.2 eq.) wasslowly added to 3-oxopentanoic acid ethyl ester (20 g, 139 mmol, 1.0eq.) at RT. After stirring for 24 h the mixture was concentrated underreduced pressure. The crude (28.5 g) was used without furtherpurification; ¹H NMR (300 MHz, CDCl₃, 300 K) δ [ppm] 7.57 (s, 1H), 4.15(q, J=7.1, 2H), 2.99-2.91 (m, 6H), 2.60 (m, 2H), 1.25 (t, J=7.1, 3H),1.02 (t, J=7.4, 3H).

Step 2: 5-Hydrazinylpyrimidine hydrochloride (A2)

In a pressure vessel pyrimidine-5-boronic acid (10 g, 80.7 mmol, 1 eq.),di-tert-butyl-azodicarboxylate (18.6 g, 80.7 mmol, 1 eq.), anhydrouscopper(II)acetate (0.5 g, 2.7 mmol, 0.033 eq) in dry methanol (320 mL)were heated at 60° C. for 1 h. The mixture was concentrated in vacuum.The residue was solved in diethyl ether and washed with sat. aq.NaHCO₃-sol. and brine. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to yield the intermediatedi-tert-butyl 1-(pyrimidin-5-yl)hydrazine-1,2-dicarboxylate.

The intermediate was solved in dioxane (130 mL) and 4M HCl in dioxane(150 mL, 592 mmol, 10.5 eq.) was slowly added. After 30 h at RT, thesolid was filtered off and washed twice with diethyl ether. The solidwas dried in vacuum yielding A2 (9.3 g, 79%). ¹H NMR (300 MHz, DMSO, 300K) δ [ppm] 10.43 (br.s, 1H), 9.05 (br.s, 3H), 8.78 (s, 1H), 8.58 (s,2H). MS (ES) C₄H₆N₄ requires: 110. found: 111 (M+H)⁺.

Step 3: Ethyl 5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxylate (A3)

To a solution of A2 (5.5 g, 37.5 mmol, 1 eq.) in dry EtOH (150 mL) wasadded Cs₂CO₃ (12.3 g, 37.5 mmol, 1 eq.). After 10 min at RT, A1 (7.1 g,35.6 mmol, 0.95 eq.) was added and the mixture was reflux for 7 h. Thereaction mixture was filtered and the filtrate was concentrated invacuum. Water was added and aq. phase was extracted with ethyl acetate.The combined organic phase was dried over MgSO₄ and concentrated invacuo.

The crude product was purified by flash chromatography on silica gel(PE/Et₂O=100:0 to 1:1) to yield the desired product A3 (2.86 g, 31%); ¹HNMR (300 MHz, CDCl₃, 300 K) δ [ppm] 9.29 (s, 1H), 8.89 (s, 2H), 8.09 (s,1H), 4.34 (q, J=7.1 Hz, 2H), 3.00 (q, J=7.5 Hz, 2H), 1.38 (t, J=7.1 Hz,3H), 1.24 (t, J=7.5 Hz, 3H). MS (ES) C₁₂H₁₄N₄O₂ requires: 246. found:247 (M+H)⁺.

Step 4: 5-Ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (A4)

To a solution of A3 (2.3 g, 9.3 mmol, 1.0 eq.) in THF (250 mL) was addeda solution of KOH (1.05 g, 18.79 mmol, 2 eq.) in water (250 mL). Themixture was stirred at 55° C. for 18 h and then evaporated in vacuum.The crude was purified by RP-flash chromatography (water, thenwater/ACN=100:0 to 95:5) yielding A4 (1.7 g, 85%); ¹H NMR (300 MHz,deuterium oxide, 300 K) δ [ppm] 9.24 (s, 1H), 9.00 (s, 2H), 7.98 (s,1H), 2.94 (q, J=7.5 Hz, 2H), 1.06 (t, J=7.5 Hz, 3H). MS (ES) C₁₀H₁₀N₄O₂requires: 218. found: 219 (M+H)⁺.

Step 4:N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide(A6)

A solution of A4 (1400 mg, 6.42 mmol, 1.2 eq.) in SOCl₂ (70 mL) washeated for 3 h at 80° C. Solvents were removed in vacuum, the crudematerial was resolved in dry toluene and evaporated again under reducedpressure to yield the acid chloride A5. The acid chloride A5 was solvedin dry pyridine (50 mL) at 0° C. and5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-amine 1 (1680 mg, 5.35mmol, 1.0 eq.) was added. After stirring at RT for 12 h, water (2 mL)was added and the mixture was evaporated under reduced pressure. Thecrude product was purified by flash chromatography on silica gel(DCM/MeOH=100:0 to 20:1), followed by RP-HPLC (column: C18), using H₂Oand ACN as eluents, the desired fractions were lyophilized to afford thetitled compound A6 (1.18 g, 2.29 mmol, 43%) as a white powder. In orderto prepare the HCl-salt, A6 was solved in ACN (40 mL) and water (20 mL).After adding aq. HCl (c=1 mol/L, 2.29 mmol, 1.0 eq) and stirring for 1h, the mixture was lyophilized yielding the HCl-salt of A6; ¹H NMR (400MHz, DMSO, 300 K) δ [ppm] 10.49 (s, 1H), 9.36 (s, 1H), 9.11 (s, 2H),8.82 (d, J=6.6 Hz, 1H), 8.57 (s, 1H), 8.13 (dd, J=13.2, 2.2 Hz, 1H),7.76 (s, 2H), 7.67 (s, 1H), 7.58 (t, J=9.0 Hz, 1H), 6.98 (d, J=6.4 Hz,1H), 4.04 (s, 6H), 3.02 (q, J=7.5 Hz, 2H), 1.10 (t, J=7.5 Hz, 3H). MS(ES) C₂₇H₂₃FN₆O₄ requires: 514. found: 515 (M+H)⁺.

IC₅₀ values ofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide(“A6”) according to the invention inhibiting RON

RON RON Compound enzyme assay cell assay No. IC₅₀ [nM] IC₅₀ [nM] “A6” 308.1

The following examples relate to medicaments:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄ 2H₂O, 28.48 g of Na₂HPO₄ 12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. The compoundN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamide

and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 2. Process for the preparationofN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand pharmaceutically usable salts, tautomers and stereoisomers thereofof claim 1, characterised in that

is reacted with

and/orN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideis converted into one of its salts.
 3. Medicaments comprising at leastN-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-(pyrimidin-5-yl)-1H-pyrazole-4-carboxamideand/or pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios of claim 1, andoptionally excipients and/or adjuvants.
 4. A method for the treatment ofcancer, septic shock, Primary open Angle Glaucoma (POAG), hyperplasia,rheumatoid arthritis, psoriasis, artherosclerosis, retinopathy,osteoarthritis, endometriosis, chronic inflammation, and/orneurodegenerative diseases, comprising administering a compound ofclaim
 1. 5. A method for the treatment of tumours, where atherapeutically effective amount of a compound of claim 1 isadministered in combination with a compound from the group 1) oestrogenreceptor modulator, 2) androgen receptor modulator, 3) retinoid receptormodulator, 4) cytotoxic agent, 5) antiproliferative agent, 6)prenyl-protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8)HIV protease inhibitor, 9) reverse transcriptase inhibitor and 10)further angiogenesis inhibitors.
 6. A method for the treatment oftumours, where a therapeutically effective amount of a compound of claim1 is administered in combination with radiotherapy and a compound fromthe group 1) oestrogen receptor modulator, 2) androgen receptormodulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5)antiproliferative agent, 6) prenyl-protein transferase inhibitor, 7)HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reversetranscriptase inhibitor and 10) further angiogenesis inhibitors.